This invention relates to analogs of clonidine, and more particularly to a novel iodinated clonidine derivatives, such as p-iodoclonidine, which in its radioactive form, for example, is useful as a probe for the identification and characterization of .alpha..sub.2 -adrenergic receptor sites.
Clonidine has the chemical formula: ##STR1## It is also known by its chemical name 2-(2,6-dichlorophenylamine)-2-imidazoline. Clonidine is known to be site-specific in that it binds preferentially to .alpha..sub.2 -adrenergic receptor sites. Clonidine activates the .alpha..sub.2 -receptor sites to produce a response similar to norepinephrine in the central nervous system.
Commercially available analogs of clonidine, such as .sup.3 H-clonidine or .sup.3 H-p-aminoclonidine, are radio-tagged with tritium (.sup.3 H) and used as probes for in vitro research on .alpha..sub.2 -adrenergic receptor sites. While such tagging does yield radio-emissive compounds, the emission is strictly of the weak beta-type, so that any interfering structure, such as nearby tissue in vivo, may completely absorb, or substantially mask, the emission before the tritium can be detected. Therefore, beta-measuring instruments must be very sensitive and intervening tissue absorption must be factored in, thereby increasing the problems created by the use of beta-emissive radio-tagged clonidine in a laboratory situation. Thus, a radio-tagged form of clonidine having a stronger emissive character would be of substantial benefit to an investigator of the pharmacological actions of clonidine at the molecular level.
Another commercially available clonidine derivative is clonidine hydrochloride which is used as an antihypertensive drug to alleviate high blood pressure. Laboratory studies have indicated that the drug and its metabolites leave the patient primarily through urinary discharge. Naturally, extensive laboratory testing has been required to show efficacy and safety of this drug. Early laboratory studies of clonidine hydrochloride in rats indicated that significant buildup of clonidine occurs in the choroid of the eye, with the possibility of retinal degeneration. Accordingly, radio-tagged clonidine would be a valuable tool for testing clonidine site specificity, build-up rates, and metabolic departure from tissues. Moreover, when clonidine is used as an antihypertensive, it initially stimulates peripheral .alpha.-adrenergic receptors, thereby producing transient vasoconstriction. Inhibition of bulbar sympathetic cardioaccelerator and sympathetic vasoconstrictor centers causes a decrease in sympathetic outflow from the brain. The binding capacity of clonidine renders it useful as a probe for the study of central nervous system-depressant effects of clonidine hydrochloride.
Advances in non-invasive imaging techniques, such as positron emission tomography, or brain scanning by computer assisted tomography, required equivalent advances in tracers which will be readily detected, have a residence time in the body sufficient to permit testing but not so long as to create undesired side effects, will be site specific so that low dosage levels are adequate, and will be non-toxic. There is, thus, a need for an improved tracer for neurological, or physiological, research and disorder diagnosis.
It is, therefore, an object of the invention to provide a novel clonidine compound which is .alpha..sub.2 -adrenergic receptor site specific.
It is another object of the invention to provide a novel clonidine compound which binds .alpha..sub.2 -adrenergic receptors better than currently used clonidine compounds.
It is a further object of the invention to provide a new radioactive clonidine compound which binds .alpha..sub.2 -adrenergic receptors with greater site specificity than currently used tritium clonidine compounds.
It is also an object of the invention to provide a strong gamma-emissive radio-tagged tracer for .alpha..sub.2 -adrenergic receptors.
It is an additional object of the invention to provide an improved tracer for neurological research on the central nervous system.
It is still another object of the invention to provide an improved tracer for diagnosis of neurological or physiological disorders by such imaging techniques as positron emission tomography, computer assisted tomography, or myocardial imaging.
It is yet an additional object of the invention to provide a tracer which is physiologically acceptable and non-toxic and which has appropriate residence time in the human body.
It is additionally an object of the invention to provide methods of preparation for iodinated clonidine compounds and radio-tagged iodinated clonidine compounds.